Repair techniques for partially ruptured, lacerated or severed tendons and ligaments (collectively denoted “cords”) vary widely depending on the nature of the injury and the particular tendon/ligament affected. There are major differences in current treatment of injured cords, depending on the species of the subject (e.g., man, mammal, bird), the extent to which access can be obtained in the least obtrusive manner, in the amount of cord excursion, the surrounding environment, the stresses to which different cords are normally subjected, and in the healing characteristics of different cords. In addition, often there is no consensus of the overall best way to repair a given cord. Examples of often injured cords having different accepted repair techniques are flexor tendons of the human hand, the anterior cruciate ligament (ACL) of the human knee and the superficial digital flexor (SDF) tendon in the horse.
For example, repair of a long flexor tendon that has been severed is typically achieved by suturing the severed tendon ends face-to-face. Historically, the joints across which the tendon acts were immobilized from three to eight weeks to protect the tendon while it healed, particularly as a freshly sutured tendon can withstand only a fraction of the tensile force to which a healthy tendon is subjected during normal use. Immobilizing the tendon, however, can result in scarring and adhesion formation along the length of the tendon, as well as can adversely affect the range of motion of the tendon, particularly in the case of flexor tendons.
More recently, it has been discovered that flexor tendons have an intrinsic capacity to heal and that limited motion will actually expedite healing. The affected joints are most often partially immobilized to prevent inadvertent application of excess force.
In the case of an anterior cruciate ligament (connecting the bottom of the femur and the top of the tibia) the stresses resulting from applied forces are much greater, particularly as there is less interaction with surrounding tissue and bone, the excursion of the cord is less, and the healing tendencies are vastly different. Despite numerous studies, there still is no universally accepted repair procedure, and prevailing procedures are difficult and intricate. The current “standard of care” remains the reconstruction of the ACL using a bone-tendon-bone autograft (i.e., harvested from the patient). However, there are multiple problems with bone-tendon-bone grafting. The intact ACL possesses important mechanoreceptive and proprioceptive capabilities. Graft reconstruction sacrifices these capabilities. Autografting involves considerable donor site morbidity. To avoid donor site morbidity, occasionally a cadaveric gall is used; however, this carries the risk of disease transmission.
In the case of partially ruptured tendons, or in surgical manipulation or reconstruction of inured tendons, a viscous solution of hyaluronan (a.k.a. hyaluronic acid (HA)) is sometimes used primarily as a lubricant within the tendon sheath. Although it functions as a moderately effective lubricant in this scenario, extensive trials in horses designed to demonstrate improved healing or a reduction in recovery time have failed to show any benefit of intralesional HA (or PSGAG, another GAG, or B-aminoproprionitrile fumarate (BAPN), all three commonly prescribed for equine lameness) over controlled exercise alone (see Dyson S, 1977 & 2004).
In previous works, and as is described in U.S. Pat. No. 5,358,973), the present inventors have shown that a combination of HA and dextran also functions as an effective lubricant, preventing formation of adhesions between apposing injured surfaces, as may often occur in injured tendons between the tendon and the sheath within, which it normally freely glides.
Regarding the occurrence of non-elastic scarring after regeneration of injured connective tissue, it is well known that healing of skin and other connective tissues is often complicated by the formation of disorganized and unsightly scar tissue, as for example in wounds related to, but not limited to, burns, incisions and ulcers. Apart from the problems of scarring in tendons and ligaments referred to above, and to the obvious aesthetic and functional complications of topical (skin) and internal scar formation following most forms of invasive surgery, and in plastic surgery (e.g. breast augmentation) in particular, the compositions disclosed can also be applied to prevent scar complications in other tissues, including, but not limited to, prevention of blindness after scarring due to eye injury, facilitation of neuronal reconnections in the central and peripheral nervous system by elimination of glial scarring, and restitution of normal gut and reproductive functionality preventing strictures and adhesions after injury incurring in the gastrointestinal and reproductive systems.
In the indications described above and in connective tissue repair in general, platelets play a common pivotal and very early role in regulating connective tissue repair. This is achieved partly by rapid early release (degranulation) of arrays of cell signaling substances (cytokines) which initiate defensive cascade reactions and partly by their ability to pull together (retract) the meshwork of fibrin fibres which form most of the hemostatic plug when blood coagulates. Platelets thus regulate fibrin clot retraction, density and porosity, which partially determine the rate at which stem cells, fibroblasts and other cells involved in the wound healing process subsequently invade the hemostatic clot (see, S. Neuss, 2010).
Indeed, platelets have long been known to play a central role in the early initiation of events leading to blood clotting (hemostasis) and the inflammatory response. During evolution, when life-threatening grossly infected dirty traumatic wounds, often with major blood loss, were common events, platelets and leukocytes played a key role in survival, functioning as a rapid early warning defense system whereby activated platelets contributed to non-adaptive immunity and inflammation by rapidly secreting chemokines and cytokines that attract leukocytes to sites of crude injury and potential sepsis.
In modern times, when surgical procedures are performed with sterile instruments in a low bioburden environment, such cascades tend to overshoot their defensive role and utility, and constitute a pathophysiological risk to the patient instead, precipitating complications such as excessive inflammation, post-operative thrombosis, macro- and micro-embolism, excess thickening of the blood vessel wall (hyperplasia) and subsequent restenosis or occlusion, catheter occlusion and shedding of harmful platelet-leukocyte microemboli, which in their turn may trigger transient ischemic attacks (TIAs), stroke or myocardial infarction or may occlude or compromise the microcirculation in, for example, transposed skin or muscle flaps during reconstructive/plastic surgery.
The formation of platelet aggregates on the surface of atheromatous plaques and subsequent organization of these white thrombi into fibrous occlusive intimal lesions is undoubtedly one mechanism by which atherosclerotic lesions progress to severe obstruction and total occlusion; coronary artery thrombosis leading to myocardial infarction almost always occurs at the site of an atheromatous plaque. Percutaneous transluminal coronary angioplasty (PTCA) has become an important procedure to re-establish blood flow to the heart through partially occluded blood vessels. Unfortunately, approximately 30% to 40% of patients that have coronary angioplasty suffer restenosis of the treated vessel within 6 months of treatment; currently, there is no reliable method of preventing vascular restenosis. A revascularization procedure such as bypass surgery or another PTCA procedure is thus often required.
These complications are particularly devastating in most forms of vascular surgery but also present a challenge in less invasive vascular procedures such as PCTA (balloon angioplasty) and in various medical conditions characterized by impaired blood supply such as, but not limited to, acute stroke, acute pancreatitis, frostbite/gangrene, loss of hearing, etc. Activated platelets are not only involved in the etiology of these conditions but are also instrumental via their interaction with leukocytes in triggering “ischemia-reperfusion injury,” which typically occurs when oxygenated blood flow is restored to an ischemic vascular bed after removal of a clamp, embolus or other obstruction to flow as, for example in organ or tissue transplantation, lysis of an occluding clot or on restoration of blood volume after hemorrhagic shock. This downstream “reperfusion injury” is generally mediated by free radical release from leukocytes which in their turn have been activated by cytokine release from activated platelets (see, Salter 2001).
Thus, interactions between activated platelets on the one hand and the endothelium, leukocytes, other cells, surfaces and fibrin in clot retraction, etc, on the other hand largely initiate and define the fate of the body's early defense against injury and sepsis. Platelet activation/degranulation following tissue injury is generally the trigger which activates leukocyte rolling and sticking to the vascular endothelium and in some injury scenarios may precede leukocyte recruitment and mobilization by as much as 3-5 hours, as for example in endotoxemic injury to the hepatic microcirculation (see, Croner, 2006). In other situations, however, this time lag may only be minutes or seconds.
Thus, events which are largely triggered by platelet activation, such as leukocyte activation, rolling and sticking to the endothelium of the microvasculature following ischemia-reperfusion (I/R) injury, may be used as surrogate indicators of underlying platelet activation.
We therefore speculate that the surprising synergistic effects of combining polysaccharides and HA which we disclose below may have a multifactorial etiology involving several interrelated synergistic factors including suppression of platelet activation, the presence of hyaluronan, and polymer-induced changes in the morphology, fragility and lysability of the fibrin clot thrilled in response to the acute injury.
In many of the surgical and medical scenarios described above, polysaccharides like dextran and, to some extent, HES, (and more recently GAGs like HA, such as discussed in U.S. Pat. No. 5,585,361) have long been used to suppress platelet hyperactivation and its inflammatory complications but often the doses required to attain effective and sustained protection are above the safe recommended doses of these agents.
For example, the risks of significant bleeding or renal complications with both dextran and HES are directly dose-related, and in situations where heparin or other anticoagulants are given at the same time, the doses of dextran or HES must be further reduced or omitted to minimize the risk of bleeding.
Both dextran and HES are also effective blood volume expanders. In some treatment scenarios, such as in stroke or threatening gangrene where the patient has not suffered significant blood loss, volume expansion may often be undesirable or contraindicated.
A synergistic interaction between dextran or other polysaccharides and HA thus offers an important therapeutic advantage in that the desired effect can be achieved by much lower and safer doses of each of the components.
An effective synergistic combination of HA together with dextran or HES, or both, therefore permits a reduction in total dextran or HES dosage without loss of the beneficial suppression of excess platelet activation, thus radically improving patient safety and offering the physician greater flexibility in devising optimal dosage regimes.
The present invention is intended to improve upon and resolve some of these known deficiencies within the relevant art discussed above.